Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier ...proteins filaggrin and loricrin.
We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 no itch to 10 worst imaginable itch), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score.
In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.
Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).
Redesigning protein surface topology to improve target binding holds great promise in the search for highly selective therapeutics. While significant binding improvements can be achieved using ...natural amino acids, the introduction of non-canonical residues vastly increases sequence space and thus the chance to significantly out-compete native partners. The potency of protein inhibitors can be further enhanced by synthesising mirror image, D-amino versions. This renders them non-immunogenic and makes them highly resistant to proteolytic degradation. Current experimental design methods often preclude the use of D-amino acids and non-canonical amino acids for a variety of reasons. To address this, we build an in silico pipeline for D-protein designs featuring non-canonical amino acids. For a test scaffold we use an existing D-protein inhibitor of VEGF: D-RFX001. We benchmark the approach by recapitulating previous experimental optimisation with canonical amino acids. Subsequent incorporation of non-canonical amino acids allows designs that are predicted to improve binding affinity by up to -7.18 kcal/mol.
Intrinsically disordered regions have been associated with various cellular processes and are implicated in several human diseases, but their exact roles remain unclear. We previously defined two ...classes of conserved disordered regions in budding yeast, referred to as "flexible" and "constrained" conserved disorder. In flexible disorder, the property of disorder has been positionally conserved during evolution, whereas in constrained disorder, both the amino acid sequence and the property of disorder have been conserved. Here, we show that flexible and constrained disorder are widespread in the human proteome, and are particularly common in proteins with regulatory functions. Both classes of disordered sequences are highly enriched in regions of proteins that undergo tissue-specific (TS) alternative splicing (AS), but not in regions of proteins that undergo general (i.e., not tissue-regulated) AS. Flexible disorder is more highly enriched in TS alternative exons, whereas constrained disorder is more highly enriched in exons that flank TS alternative exons. These latter regions are also significantly more enriched in potential phosphosites and other short linear motifs associated with cell signaling. We further show that cancer driver mutations are significantly enriched in regions of proteins associated with TS and general AS. Collectively, our results point to distinct roles for TS alternative exons and flanking exons in the dynamic regulation of protein interaction networks in response to signaling activity, and they further suggest that alternatively spliced regions of proteins are often functionally altered by mutations responsible for cancer.
Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells affected by radiation to cause the GI ...syndrome are derived from the epithelium or endothelium and whether the target cells die by apoptosis or other mechanisms are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after sub-total-body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not from endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by the death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.
In all known fermionic superfluids, Cooper pairs are composed of spin-1/2 quasi-particles that pair to form either spin-singlet or spin-triplet bound states. The "spin" of a Bloch electron, however, ...is fixed by the symmetries of the crystal and the atomic orbitals from which it is derived and, in some cases, can behave as if it were a spin-3/2 particle. The superconducting state of such a system allows pairing beyond spin-triplet, with higher spin quasi-particles combining to form quintet or septet pairs. We report evidence of unconventional superconductivity emerging from a spin-3/2 quasi-particle electronic structure in the half-Heusler semimetal YPtBi, a low-carrier density noncentrosymmetric cubic material with a high symmetry that preserves the
-like
= 3/2 manifold in the Bi-based Γ
band in the presence of strong spin-orbit coupling. With a striking linear temperature dependence of the London penetration depth, the existence of line nodes in the superconducting order parameter Δ is directly explained by a mixed-parity Cooper pairing model with high total angular momentum, consistent with a high-spin fermionic superfluid state. We propose a
⋅
model of the
= 3/2 fermions to explain how a dominant
= 3 septet pairing state is the simplest solution that naturally produces nodes in the mixed even-odd parity gap. Together with the underlying topologically nontrivial band structure, the unconventional pairing in this system represents a truly novel form of superfluidity that has strong potential for leading the development of a new series of topological superconductors.
The intrinsically disordered regions of eukaryotic proteomes are enriched in short linear motifs (SLiMs), which are of crucial relevance for cellular signaling and protein regulation; many mediate ...interactions by providing binding sites for peptide‐binding domains. The vast majority of SLiMs remain to be discovered highlighting the need for experimental methods for their large‐scale identification. We present a novel proteomic peptide phage display (ProP‐PD) library that displays peptides representing the disordered regions of the human proteome, allowing direct large‐scale interrogation of most potential binding SLiMs in the proteome. The performance of the ProP‐PD library was validated through selections against SLiM‐binding bait domains with distinct folds and binding preferences. The vast majority of identified binding peptides contained sequences that matched the known SLiM‐binding specificities of the bait proteins. For SHANK1 PDZ, we establish a novel consensus TxF motif for its non‐C‐terminal ligands. The binding peptides mostly represented novel target proteins, however, several previously validated protein–protein interactions (PPIs) were also discovered. We determined the affinities between the VHS domain of GGA1 and three identified ligands to 40–130 μm through isothermal titration calorimetry, and confirmed interactions through coimmunoprecipitation using full‐length proteins. Taken together, we outline a general pipeline for the design and construction of ProP‐PD libraries and the analysis of ProP‐PD‐derived, SLiM‐based PPIs. We demonstrated the methods potential to identify low affinity motif‐mediated interactions for modular domains with distinct binding preferences. The approach is a highly useful complement to the current toolbox of methods for PPI discovery.
The intrinsically disordered regions of eukaryotic proteomes are enriched in short linear motifs. These compact interfaces provide binding sites for peptide‐binding domains. We present a novel proteomic peptide phage display library that displays peptides directly mapping to disordered regions of the human proteome and validate its performance. This opens for large‐scale analysis of motif‐based interactions.
Background Cigarette smoke–induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been ...hampered by the lack of an animal model that mimics the human disease in a short timeframe. Objectives We sought to create an early-onset mouse model of cigarette smoke–induced COPD that develops the hallmark features of the human condition in a short time-frame. We also sought to use this model to better understand pathogenesis and the roles of macrophages and mast cells (MCs) in patients with COPD. Methods Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathologic features of COPD was assessed. The roles of macrophages and MC tryptase in pathogenesis were evaluated by using depletion and in vitro studies and MC protease 6–deficient mice. Results After just 8 weeks of smoke exposure, wild-type mice had chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart and increased susceptibility to respiratory tract infections also were observed. Macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced proinflammatory responses from cultured macrophages. Conclusion A short-term mouse model of cigarette smoke–induced COPD was developed in which the characteristic features of the disease were induced more rapidly than in existing models. The model can be used to better understand COPD pathogenesis, and we show a requirement for macrophages and tryptase-expressing MCs.
Severe steroid-resistant asthma is clinically important, as patients with this form of the disease do not respond to mainstay corticosteroid therapies. The heterogeneity of this form of asthma and ...poor understanding of the pathological mechanisms involved hinder the identification of therapeutic targets and the development of more effective therapies. A major limiting factor in the understanding of severe steroid-resistant asthma is the existence of multiple endotypes represented by different immunological and inflammatory phenotypes, particularly in adults. Several clinical and experimental studies have revealed associations between specific respiratory infections and steroid-resistant asthma in adults. Here, we discuss recent findings from other authors as well as our own studies that have developed novel experimental models for interrogating the association between respiratory infections and severe steroid-resistant asthma. These models have enabled the identification of new therapies using macrolides, as well as several novel disease mechanisms, including the microRNA-21/phosphoinositide 3-kinase/histone deacetylase 2 axis and NLRP3 inflammasomes, and highlight the potential of these mechanisms as therapeutic targets.
Most studies of protein networks operate on a high level of abstraction, neglecting structural and chemical aspects of each interaction. Here, we characterize interactions by using atomic-resolution ...information from three-dimensional protein structures. We find that some previously recognized relationships between network topology and genomic features (e.g., hubs tending to be essential proteins) are actually more reflective of a structural quantity, the number of distinct binding interfaces. Subdividing hubs with respect to this quantity provides insight into their evolutionary rate and indicates that additional mechanisms of network growth are active in evolution (beyond effective preferential attachment through gene duplication).
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